title: Death receptor 6 (DR6) antagonist antibody is neuroprotective in the mouse SOD1G93A model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of motor neurons, axon degeneration, and denervation of neuromuscular junctions (NMJ). Here we show that death receptor 6 (DR6) levels are elevated in spinal cords from post-mortem samples of human ALS and from SOD1(G93A) transgenic mice, and DR6 promotes motor neuron death through activation of the caspase 3 signaling pathway. Blocking DR6 with antagonist antibody 5D10 promotes motor neuron survival in vitro via activation of Akt phosphorylation and inhibition of the caspase 3 signaling pathway, after growth factor withdrawal, sodium arsenite treatment or co-culture with SOD1(G93A) astrocytes. Treatment of SOD1(G93A) mice at an asymptomatic stage starting on the age of 42 days with 5D10 protects NMJ from denervation, decreases gliosis, increases survival of motor neurons and CC1(+) oligodendrocytes in spinal cord, decreases phosphorylated neurofilament heavy chain (pNfH) levels in serum, and promotes motor functional improvement assessed by increased grip strength. The combined data provide clear evidence for neuroprotective effects of 5D10. Blocking DR6 function represents a new approach for the treatment of neurodegenerative disorders involving motor neuron death and axon degeneration, such as ALS.
authors.affiliation: Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: G
authors.initials: G
authors.lastname: Huang
authors.forename: X
authors.initials: X
authors.lastname: Lee
authors.forename: Y
authors.initials: Y
authors.lastname: Bian
authors.forename: Z
authors.initials: Z
authors.lastname: Shao
authors.forename: G
authors.initials: G
authors.lastname: Sheng
authors.forename: R B
authors.initials: RB
authors.lastname: Pepinsky
authors.forename: S
authors.initials: S
authors.lastname: Mi
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology* / Q000627:therapeutic use*; D001369:Axons / Q000187:drug effects / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D011180:Postmortem Changes; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D019138:Antibodies, Blocking; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; C485251:Tnfrsf21 protein, mouse; D013482:Superoxide Dismutase; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3